Chimeric receptor polypeptides and uses thereof

Abstract

Provided is a chimeric receptor polypeptide comprising: a) an extracellular target binding domain; b) an extracellular TCR binding domain; c) a transmembrane domain comprising a transmembrane domain of a first TCR subunit; and/or d) an intracellular domain comprising an intracellular domain of a second TCR subunit. Also provided are nucleic acids encoding such chimeric receptor polypeptide and immune cells expressing such chimeric receptor polypeptide and uses thereof.

1 . A chimeric receptor polypeptide comprising:
 a) an extracellular target binding domain;   b) an extracellular T-cell receptor (TCR) binding domain;   c) a transmembrane domain comprising a transmembrane domain of a first TCR subunit; and   d) an intracellular domain comprising an intracellular domain of a second TCR subunit,   wherein the first TCR subunit and the second TCR subunit are each independently selected from the group consisting of CD3ε, CD3γ, CD3δ, TCRα, TCRβ, TCRγ, and TCRδ.   
     
     
         2 . The chimeric receptor polypeptide of  claim 1 , wherein the extracellular TCR binding domain comprises a TCR antigen binding domain specifically recognizing a TCR subunit selected from the group consisting of TCRα, TCRβ, TCRγ, TCRδ, CD3ε, CD3δ, CD3γ, and CD3ζ. 
     
     
         3 . (canceled) 
     
     
         4 . The chimeric receptor polypeptide of  claim 2 , wherein the TCR antigen binding domain is a single chain Fv (scFv) or a single domain antibody (sdAb). 
     
     
         5 . The chimeric receptor polypeptide of  claim 1 , wherein the extracellular TCR binding domain comprises two or more TCR antigen binding domains arranged in tandem. 
     
     
         6 . The chimeric receptor polypeptide of  claim 1 , wherein the chimeric receptor polypeptide does not comprise an extracellular domain of the first TCR subunit, the second TCR subunit, or any TCR subunit. 
     
     
         7 . (canceled) 
     
     
         8 . The chimeric receptor polypeptide of  claim 1 , wherein the chimeric receptor polypeptide does not comprise an intracellular co-stimulatory domain. 
     
     
         9 . The chimeric receptor polypeptide of  claim 1 , wherein the first TCR subunit and the second TCR subunit are different. 
     
     
         10 - 11 . (canceled) 
     
     
         12 . The chimeric receptor polypeptide of  claim 1 , wherein the first TCR subunit and the second TCR subunit are the same. 
     
     
         13 - 19 . (canceled) 
     
     
         20 . The chimeric receptor polypeptide of  claim 1 , wherein the extracellular target binding domain is at the N-terminus of the extracellular TCR binding domain. 
     
     
         21 . The chimeric receptor polypeptide of  claim 1 , wherein the extracellular target binding domain is at the C-terminus of the extracellular TCR binding domain. 
     
     
         22 . The chimeric receptor polypeptide of  claim 1 , wherein the extracellular target binding domain comprises a target antigen binding domain specifically recognizing a target antigen. 
     
     
         23 . The chimeric receptor polypeptide of  claim 22 , wherein the target antigen binding domain is an scFv, an sdAb, or a designed ankyrin repeat protein (DARPin). 
     
     
         24 . The chimeric receptor polypeptide of  claim 22 , wherein the extracellular target binding domain comprises two or more target antigen binding domains arranged in tandem. 
     
     
         25 - 26 . (canceled) 
     
     
         27 . The chimeric receptor polypeptide of  claim 22 , wherein the target antigen is selected from the group consisting of BCMA, NY-ESO-1, VEGFR2, MAGE-A3, AFP, CD4, CD19, CD20, CD22, CD30, CD33, CD38, CD70, CD123, CEA, EGFR (such as EGFRvIII), GD2, GPC-2, GPC3, HER2, LILRB4, IL-13Rα2, IGF1R, mesothelin, PSMA, ROR1, WT1, NKG2D, CLL1, TGFaRII, TGFbRII, CCR5, CXCR4, CCR4, HPV related antigen, and EBV related antigen (such as LMP1 and LMP2). 
     
     
         28 - 31 . (canceled) 
     
     
         32 . The chimeric receptor polypeptide of  claim 1 , comprising from the N-terminus to the C-terminus: 
 a) optional signal peptide - extracellular target binding domain - optional first linker -extracellular TCR binding domain - optional second linker - optional hinge region -transmembrane domain - intracellular domain; or   b) optional signal peptide - extracellular TCR binding domain - optional first linker -extracellular target binding domain - optional second linker - optional hinge region -transmembrane domain - intracellular domain.   
     
     
         33 . An isolated nucleic acid encoding the chimeric receptor polypeptide of  claim 1 . 
     
     
         34 . A nucleic acid vector comprising one or more nucleic acids of  claim 33 . 
     
     
         35 . An isolated immune cell comprising one or more chimeric receptor polypeptides of  claim 1 . 
     
     
         36 - 41 . (canceled) 
     
     
         42 . A pharmaceutical composition comprising the isolated immune cell of  claim 35 , and an optional pharmaceutically acceptable excipient. 
     
     
         43 . A method of treating a disease in an individual, comprising administering to the individual an effective amount of the pharmaceutical composition of  claim 42 . 
     
     
         44 - 46 . (canceled)